Patients with type 1 diabetes mellitus (T1DM) experience, on average, 2 to 3 hypoglycemic episodes per week. This study investigated the effect of hypoglycemia on cerebral glucose metabolism in patients with uncomplicated T1DM. For this purpose, hyperinsulinemic euglycemic and hypoglycemic glucose clamps were performed on separate days, using [1-13 C]glucose infusion to increase plasma 13 C enrichment. In vivo brain 13 C magnetic resonance spectroscopy was used to measure the time course of 13 C label incorporation into different metabolites and to calculate the tricarboxylic acid cycle flux (V TCA ) by a one-compartment metabolic model. We found that cerebral glucose metabolism, as reflected by the V TCA , was not significantly different comparing euglycemic and hypoglycemic conditions in patients with T1DM. However, the V TCA was inversely related to the HbA 1C and was, under hypoglycemic conditions, approximately 45% higher than that in a previously investigated group of healthy subjects. These data suggest that the brains of patients with T1DM are better able to endure moderate hypoglycemia than those of subjects without diabetes. IntroductionPatients with type 1 diabetes mellitus (T1DM) experience on average 2 hypoglycemic episodes per week and 1 severe episode of hypoglycemia each year (1). Because the brain depends almost exclusively on glucose, recurrent hypoglycemia may be a threat for cognitive dysfunction and cerebral damage. Patients with T1DM are at increased risk for accelerated cognitive decline and possibly for dementia (2, 3). Interestingly, however, patients with T1DM enduring recurrent episodes of severe hypoglycemia do not appear at greater risk of developing cognitive function impairment than patients without such a history (4). This suggests that recurrent hypoglycemia can induce protective adaptations with respect to cerebral glucose metabolism or that hyperglycemia is at least as detrimental for the brain as hypoglycemia.Recently, we showed that brain glucose metabolism in healthy subjects at glucose levels of approximately 3 mmol/l did not differ from that at normal glucose levels, as reflected by similar tricarboxylic acid (TCA) cycle rates (V TCA ) (5). This remarkable maintenance of normal V TCA during symptomatic hypoglycemia indicates that the glucose threshold for effects on cerebral metabolism lies below 3 mmol/l, either because the brain can endure low glucose levels or because entrance of nonglucose energy substrates such as lactate compensates for the fall in glucose (6-9). Whether these findings can be extrapolated to patients with T1DM remains to be determined.This study was therefore undertaken to investigate the effect of hypoglycemia on brain glucose metabolism in a representative group of patients with longstanding, uncomplicated, reasonably well-controlled T1DM. To do so, we used 13 C magnetic resonance spectroscopy (MRS) of the human brain during euglycemic and hypoglycemic glucose clamps with infusion of [1-13 C]glucose, as described previously (5, 10). With this appro...

The objective of this study was to investigate the relationship between plasma and brain glucose levels during euglycemia and hypoglycemia in healthy subjects and patients with type 1 diabetes mellitus (T1DM). Hyperinsulinemic euglycemic (5 mmol/L) and hypoglycemic (3 mmol/L) [1-13C]glucose clamps were performed in eight healthy subjects and nine patients with uncomplicated T1DM (HbA1c 7.7 ± 1.4%). Brain glucose levels were measured by 13C magnetic resonance spectroscopy. Linear regression analysis was used to fit the relationship between plasma and brain glucose levels and calculate reversible Michaelis-Menten (MM) kinetic parameters. Brain glucose values during euglycemia (1.1 ± 0.4 μmol/g vs. 1.1 ± 0.3 μmol/g; P = 0.95) and hypoglycemia (0.5 ± 0.2 μmol/g vs. 0.6 ± 0.3 μmol/g; P = 0.52) were comparable between healthy subjects and T1DM patients. MM kinetic parameters of combined data were calculated to be maximum transport rate/cerebral metabolic rate of glucose (Tmax/CMRglc) = 2.25 ± 0.32 and substrate concentration at half maximal transport (Kt) = 1.53 ± 0.88 mmol/L, which is in line with previously published data obtained under hyperglycemic conditions. In conclusion, the linear MM relationship between plasma and brain glucose can be extended to low plasma glucose levels. We found no evidence that the plasma to brain glucose relationship or the kinetics describing glucose transport over the blood–brain barrier differ between healthy subjects and patients with uncomplicated, reasonably well-controlled T1DM.

OBJECTIVETo investigate the effect of acute insulin-induced hypoglycemia on cerebral glucose metabolism in healthy humans, measured by 13C magnetic resonance spectroscopy (MRS).RESEARCH DESIGN AND METHODSHyperinsulinemic glucose clamps were performed at plasma glucose levels of 5 mmol/L (euglycemia) or 3 mmol/L (hypoglycemia) in random order in eight healthy subjects (four women) on two occasions, separated by at least 3 weeks. Enriched [1-13C]glucose 20% w/w was used for the clamps to maintain stable plasma glucose labeling. The levels of the 13C-labeled glucose metabolites glutamate C4 and C3 were measured over time in the occipital cortex during the clamp by continuous 13C MRS in a 3T magnetic resonance scanner. Time courses of glutamate C4 and C3 labeling were fitted using a one-compartment model to calculate metabolic rates in the brain.RESULTSPlasma glucose 13C isotopic enrichment was stable at 35.1 ± 1.8% during euglycemia and at 30.2 ± 5.5% during hypoglycemia. Hypoglycemia stimulated release of counterregulatory hormones (all P < 0.05) and tended to increase plasma lactate levels (P = 0.07). After correction for the ambient 13C enrichment values, label incorporation into glucose metabolites was virtually identical under both glycemic conditions. Calculated tricarboxylic acid cycle rates (VTCA) were 0.48 ± 0.03 μmol/g/min during euglycemia and 0.43 ± 0.08 μmol/g/min during hypoglycemia (P = 0.42).CONCLUSIONSThese results indicate that acute moderate hypoglycemia does not affect fluxes through the main pathways of glucose metabolism in the brain of healthy nondiabetic subjects.

The effect of insulin-induced hypoglycemia on cerebral glucose metabolism is largely unknown. 13 C MRS is a unique tool to study cerebral glucose metabolism, but the concurrent requirement for [1-13 C]glucose administration limits its use under hypoglycemic conditions. To facilitate 13C MRS data analysis we designed separate [1-13 C]glucose infusion protocols for hyperinsulinemic euglycemic and hypoglycemic clamps in such a way that plasma isotopic enrichment of glucose was stable and comparable under both glycemic conditions. 13 C MR spectra were acquired with optimized 13 C MRS measurement techniques to obtain high quality 13 C MR spectra with these protocols.

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